Unknown,Transcriptomics,Genomics,Proteomics

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The biological and molecular heterogeneity of breast cancers correlate with their cancer stem cell content

ABSTRACT: Pathways that govern normal stem cell (SC) function are often subverted in cancer. Here, we report the isolation to near purity of human normal mammary SC (hNMSCs), from cultured mammospheres, based on their ability to retain the lipophilic dye PKH26 as a consequence of their quiescent nature. We demonstrated that PKH26-positive cells possess all the characteristics of hNMSCs. The transcriptional profile of PKH26-positive cells (hNMSC signature) was able to predict biological and molecular features of breast cancers. By using markers of the hNMSC signature, we could prospectively isolate SCs from the normal gland and from breast tumors. Poorly-differentiated aggressive (G3) cancers displayed higher content of prospectively isolated cancer SCs, than well-differentiated less aggressive (G1) cancers. By comparing G3 and G1 tumors in xenotransplantation experiments, we directly demonstrated that G3s are enriched in cancer SCs. Our data support the notion that the heterogeneous phenotypical and molecular traits of human breast cancers are a function of their SC content. Epithelial cells, from reductive mammoplasties, labeled with PKH26 (Sigma, 10-7 M, 5 min) and subjected to FACS analysis using a FACS Vantage SE flow cytometer (Becton&Dickinson) to yield PKH-POS and PKH-NEG cells, were prepared for RNA extraction and hybridization on Affymetrix microarrays. Three independent pools of cells were used, and six Gene Expression Arrays were obtained. No replicates are available.

ORGANISM(S): Homo sapiens

SUBMITTER: Stefano Confalonieri

PROVIDER: E-GEOD-18931 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content.

Pece Salvatore S Tosoni Daniela D Confalonieri Stefano S Mazzarol Giovanni G Vecchi Manuela M Ronzoni Simona S Bernard Loris L Viale Giuseppe G Pelicci Pier Giuseppe PG Di Fiore Pier Paolo PP

Cell 20100101 1

Pathways that govern stem cell (SC) function are often subverted in cancer. Here, we report the isolation to near purity of human normal mammary SCs (hNMSCs), from cultured mammospheres, on the basis of their ability to retain the lipophilic dye PKH26 as a consequence of their quiescent nature. PKH26-positive cells possess all the characteristics of hNMSCs. The transcriptional profile of PKH26-positive cells (hNMSC signature) was able to predict biological and molecular features of breast cancer ...[more]

PMID: 20074520

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Project description:Histological grading of breast cancer defines morphological subtypes informative of metastatic potential, although not without considerable inter-observer disagreement and clinical heterogeneity particularly among the moderately differentiated grade II (G2) tumors. We posited that a gene expression signature capable of discerning tumors of grade I (G1) and grade III (G3) histology might provide a more objective measure of grade with prognostic benefit for patients with moderately differentiated disease. To this end, we studied the expression profiles of 347 primary invasive breast tumors analyzed on Affymetrix microarrays. Using class prediction algorithms, we identified 264 robust grade-associated markers, six of which could accurately classify G1 and G3 tumors, and separate G2 tumors into two highly discriminant classes (termed G2a and G2b genetic grades) with patient survival outcomes highly similar to those with G1 and G3 histology, respectively. Statistical analysis of conventional clinical variables further distinguished G2a and G2b subtypes from each other, but also from histologic G1 and G3 tumors. In multivariate analyses, genetic grade was consistently found to be an independent prognostic indicator of disease recurrence comparable to that of lymph node status and tumor size. When incorporated into the Nottingham Prognostic Index, genetic grade enhanced detection of patients with less harmful tumors, likely to benefit little from adjuvant therapy. Our findings show that a genetic grade signature can improve prognosis and therapeutic planning for breast cancer patients, and support the view that low and high grade disease, as defined genetically, reflect independent pathobiological entities rather than a continuum of cancer progression. Three separate breast cancer cohorts were analyzed: 1) Uppsala (n=249), 2) Stockholm (n=58), 3) Singapore (n=40). The Uppsala and Singapore data can be accessed here. The Stockholm cohort data can be accessed at GEO Series GSE1456. Keywords: Tumor sample comparisons

Dataset Information

The biological and molecular heterogeneity of breast cancers correlate with their cancer stem cell content

Publications

Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content.

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